Products and methods for brachytherapy

ABSTRACT

A radioactive member for use in brachytherapy comprising a hollow elongate bioabsorbable suture member with radioactive seeds and spacer members without different coloration and diameter from the radioactive seeds alternately disposed therein, and methods for the manufacture and the use thereof. The radioactive members may be used in the treatment of, for example, prostate cancer.

FIELD OF INVENTION

[0001] The present invention relates generally to radiotherapy. Morespecifically, it relates to radioactive sources for use in brachytherapyand to methods for the preparation of such sources.

BACKGROUND OF THE INVENTION

[0002] Brachytherapy is a general term covering medical treatment whichinvolves the placement of a radioactive source near a diseased tissueand may involve the temporary or permanent implantation or insertion ofa radioactive source into the body of a patient. The radioactive sourceis thereby located in proximity to the area of the body which is beingtreated. This has the advantage that a high dose of radiation may bedelivered to the treatment site with relatively low dosages of radiationto surrounding or intervening healthy tissue.

[0003] Brachytherapy has been proposed for use in the treatment of avariety of conditions, including arthritis and cancer, for examplebreast, brain, liver and ovarian cancer and especially prostate cancerin men (see for example J. C. Blasko et al., The Urological Clinics ofNorth America, 23, 633-650 (1996), and H. Ragde et al., Cancer, 80,442-453 (1997)). Prostate cancer is the most common form of malignancyin men in the USA, with more than 44,000 deaths in 1995 alone. Treatmentmay involve the temporary implantation of a radioactive source for acalculated period, followed by its removal. Alternatively, theradioactive source may be permanently implanted in the patient and leftto decay to an inert state over a predictable time. The use of temporaryor permanent implantation depends on the isotope selected and theduration and intensity of treatment required.

[0004] Permanent implants for prostate treatment comprise radioisotopeswith relatively short half lives and lower energies relative totemporary sources. Examples of permanently implantable sources includeiodine-125 or palladium-103 as the radioisotope. The radioisotope isgenerally encapsulated in a casing such as titanium to form a “seed”which is then implanted. Temporary implants for the treatment ofprostate cancer may involve iridium-192 as the radioisotope.

[0005] Conventional radioactive sources for use in brachytherapy includeso-called seeds, which are sealed containers, for example of titanium,containing the radioisotope within a sealed chamber but permittingradiation to exit through the container/chamber walls (U.S. Pat. No.4,323,055 and U.S. Pat. No. 3,351,049). Such seeds are only suitable foruse with radioisotopes which emit radiation which can penetrate thechamber/container walls. Therefore, such seeds are generally used withradioisotopes which emit γ-radiation or low-energy X-rays, rather thanwith β-emitting radioisotopes.

[0006] Radioactive seeds are generally loaded into needles, with theneedles then being inserted into the treatment site, such as prostate,using ultrasound imaging to guide the insertion process. The radioactiveseeds are either positioned independently within the needles and henceare located independently within the treatment site after they have beenmoved out of the needle, or they are connected in a string arrangementby being loaded within a hollow, absorbable suture member.

[0007] U.S. Pat. No. 5,460,592 discloses a method and apparatus fortransporting a radioactive device. The device comprises a flexible,elongated woven or braided bio-absorbable carrier material having spacedradioactive seeds disposed therein. On heating, the carrier materialholding the seeds becomes semi-rigid. A length of the semi-rigid carriermaterial with radioactive seeds disposed therein may then be loaded intoa conventional, hollow metal dispensing needle or applicator cartridgewhich is used to implant the radioactive seeds into or contiguous to thetreatment site, for example a tumour.

[0008] A commercial product consisting of iodine-125 seeds regularlyspaced at between 0.6 and 1.2 cm centre to centre inside a braided,semi-rigid bioabsorbable suture material is available from Medi-PhysicsInc. under the trade name I-125 RAPID Strand™. This product may be usedto treat conditions such as head and neck cancers, including those ofthe mouth, lips and tongue, brain tumours, lung tumours, cervicaltumours, vaginal tumours and prostate cancer.

[0009] One advantage of this type of suture/radioactive seed combinationis that the radioactive seeds are implanted or inserted into a patientwith a predetermined spacing, depending on their spacing in the suturematerial. The bioabsorbable material is then slowly absorbed into thepatient's body to leave the spaced seeds in position. This predeterminedspacing and the semi-rigid nature of the suture aids a physician incalculating both the total radiation dose and the dose profile whichwill be delivered by the seeds inside a patient's body, and also aids inaccurate placement of the seeds. In addition, more than one seed isimplanted at once, so lessening the time taken for implantation overthat required for the placement of individual loose seeds. The risk ofseed migration away from the site of implantation is also reduced (Tapenet al., Int. J. Radiation Oncology Biol. Phys., vol. 42(5), pages1063-1067, 1998).

[0010] Another advantage of the hollow suture combination overindependent seeds approach is that the independent seeds, even once inthe treatment site, for example prostate, could migrate out of theprostate to various other locations in the body, including lungs.Migrated seeds can reduce implant quality and also potentially harm thepatient.

[0011] However, this hollow suture combination has limitations on longaxis strength due to the void areas, introduced into the arrangementduring manufacturing, used for the spacing between the radioactiveseeds. This void area long axis strength is limited to the strength ofthe suture material. Although the void area strength is increased duringthe heat stiffening manufacturing process, the resulting strength isstill not ideal. Due to this limitation, the suture combination cansometimes jam within the insertion needle, resulting in a collapsing ofthe suture combination in the void area between the radioactive seeds.This condition requires removal of the needle from the prostate and thesubsequent reloading of the needle with independent radioactive seeds.This alteration of technique is time-consuming and expensive in nature.

[0012] One approach to remedy the situation is disclosed in U.S. Pat.No. 6,264,600. It discloses a method and apparatus including a hollowsuture with alternating plurality of radioactive seeds and intermediatespacers. While this suture/seed combination offers stronger long axisstrength, there are several areas that can be improved upon.

[0013] First, there is still need for even more long axis strength toreduce the possibilities of suture jamming within the insertion needle.

[0014] Further, both hollow suture/seed combination and current hollowsuture/seed/spacer combination is singular in color, with onlydimensional differences in seeds and void areas of the assembly. Thislimitation can cause uncertainty in preparing the combination inimplant. The current fixture only allows cutting in the void areas ofthe suture combination, away from the critical radioactive seedcomponent. However, this becomes impossible once the suture combinationis removed from the fixture.

[0015] Finally, current suture/seed/spacer combination has similardiameters for both seed and spacer. This lack of dimensional differencemakes cutting more difficult.

[0016] There is therefore a need for an improved radioactive sourcewhich does not suffer from all the disadvantages of the known sources,and which can preferably be produced using an automated manufacturingprocess.

SUMMARY OF THE INVENTION

[0017] In one aspect of the invention there is therefore provided aradioactive member for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with a plurality of radioactive seeds andspacer members disposed alternately therein, wherein the spacer membersare dyed with a different color from that of the undyed radioactiveseeds and of different diameter from that of the radioactive seeds. Theradioactive seeds and the spacer members are preferably retained thereinby deformation of the suture member on heating, followed by subsequentcooling.

[0018] In a further aspect of the invention, there is provided aradioactive member for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with one or more slots therein in which oneor more radioactive seeds and spacer members are disposed alternately ina spaced relationship, wherein the spacer members are dyed with adifferent color from that of the undyed radioactive seeds and ofdifferent diameter from that of the radioactive seeds. Preferably, thesuture member is essentially stiff. The slots may comprise a continuousgroove or a series of discrete openings longitudinally spaced along thesuture material. Preferably, the radioactive seeds and spacers aresecurely retained in the suture member by heat sealing.

[0019] As a further feature of the invention there is provided a methodfor the production of a radioactive member for use in brachytherapycomprising an elongate, bioabsorbable suture member with radioactiveseeds and spacer members disposed alternately therein, said methodcomprising the steps of:

[0020] a) providing a hollow bioabsorbable suture member,

[0021] b) providing a plurality of radioactive seeds,

[0022] c) providing a plurality of bioabsorbable spacer members, whereinthe spacer members are dyed with a different color from that of theundyed radioactive seeds and of different diameter from that ofradioactive seeds,

[0023] d) heating the radioactive seeds to a temperature above themelting or softening temperature of the suture material,

[0024] e) placing the heated seeds and spacer members alternately ontothe suture member in a predetermined pattern whereby the suture membermelts or deforms around each source and spacer member, and

[0025] f) cooling the suture member such that it solidifies or hardensabout each source and spacer member so as to securely retain each sourcein place.

[0026] In an alternative embodiment of the method, in steps d) and e),the suture member may itself be at an elevated temperature (at which itdoes not lose its integrity), for example following extrusion, and theradioactive seeds and spacer members then placed onto the suture membersuch that they are held in place as it cools. In such a method, theradioactive seeds may be cold or may themselves also be heated.

[0027] In step e), an external force may also optionally be applied todeform or to further deform the suture member around the radioactiveseeds and the spacer members. For example, heated plates may be appliedto the exterior of the suture member to further melt the suture memberaround the radioactive seeds and the spacer members to hold them inplace.

[0028] In yet another embodiment of the method, it further comprises astep of sterilizing the radioactive member.

[0029] In another embodiment of the invention, there is provided amethod of using the radioactive member for brachytherapy, said methodcomprising:

[0030] a) cutting the radioactive member at one of the spacer members toa prescribed length according to the prescribed implant plan;

[0031] b) inserting the cut radioactive member into a hub end of ahollow insertion needle suitable for insertion into a prescribetreatment area, so that the entire radioactive member is inside theneedle;

[0032] c) pushing the radioactive member through the hollow insertionneedle with a needle stylet, until the leading tip of the radioactivemember reaches a needle plugging media;

[0033] d) inserting the loaded insertion needle into the prescribedtreatment area of a patient;

[0034] e) removing the insertion needle from around the radioactivemember, leaving the radioactive member in the prescribed treatment areaof the patient.

[0035] In yet another embodiment of the invention, there is providedanother method of using the radioactive member for brachytherapy, saidmethod comprising:

[0036] a) inserting an insertion needle into a prescribed treatment areaof a patient;

[0037] b) cutting the radioactive member at one of the spacer members toa prescribed length according to the prescribed implant plan;

[0038] c) loading the radioactive member into an after-loading device;

[0039] d) transferring the radioactive member in the after-loadingdevice to the insertion needle where it mates into the insertion needlehub;

[0040] e) applying a stylet to advance the radioactive member throughthe after-loading device into the insertion needle, and finally into thepatient;

[0041] f) removing the insertion needle and the after-loading device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042]FIG. 1 is a cross-sectional view of the improved suturecombination of the present invention.

[0043]FIG. 2 shows a partial, exploded view of the elongated seed suturemember and radioactive seeds located in first and second recesses of ajig member with knife edge slots traversing the first and secondrecesses.

[0044]FIG. 3 shows a segment of the prepared radioactive member beingloaded into a brachytherapy needle before implantation into a patient.

[0045]FIG. 4 shows a segment of the prepared device being loaded into aafter-loading device and then into a brachytherapy needle at the time ofimplantation into a patient.

DETAILED DESCRIPTION OF THE INVENTION

[0046] Referring to the drawings, FIG. 1 shows a cross-section of oneembodiment of the invention: a radioactive member for use inbrachytherapy comprising a hollow elongate bioabsorbable suture member 3with radioactive seeds 2 and spacer members 1 alternately dispersedtherein.

[0047] Radioactive seeds 2 are typically 0.5 mm to 1 mm in diameter and4 mm to 5 mm in length. However, dimensions of radioactive seeds canvary. The spacer members can be of fixed or variable length between eachradioactive seed. The spacer members are on both the leading andtrailing edges of the radioactive member.

[0048] Coloration in spacer members may be used to create a color schemeto easily identify components inside the suture member. Spacer members 1may be dyed, for example, violet, to distinguish from undyed suturemember 3. Diameter size of the spacer members 1, in comparison todiameter size of the radioactive seeds 2, may be different, such asreduced, to easily identify components inside the suture member 3. Heatstiffening of the radioactive member during the manufacturing processincreases the long axis rigidity, adheres the suture member 3 to theinternal radioactive seeds 2 and spacer members 1, and allows colorationto transfer from the spacer members 1 to suture member 3 for easyidentification of components.

[0049] The suture member and spacer member can be made of the samematerial. They may be any non-toxic, bio-compatible, bioabsorbablematerial or a mixture of such materials. As used herein, a bioabsorbablematerial is any material of which a substantial portion will bemetabolized within a patient's body and ultimately eliminated therefrom.Suitable bioabsorbable materials include poly(glycolic acid) (PGA) andpoly(lactic acid) (PLA), polyester amides of glycolic or lactic acidssuch as polymers and copolymers of glycolate and lactate, polydioxanoneand the like. Such materials are more fully described in U.S. Pat. No.5,460,592 which is hereby incorporated by reference. Suitablecommercially available polymers include polyglycaprone 25 (MONCRYL™),polyglactin 910 (VICRYL™) and polydioanone (PDS II), all available fromEthicon, Inc. of New Jersey, U.S.A.

[0050] Other suitable bioabsorbable polymers and polymer compositionsthat may be used in this invention are described in the followingpatents which are hereby incorporated by reference: U.S. Pat. No.4,052,988 which discloses compositions comprising extruded and orientedfilaments of polymers of p-dioxanone and 1,4-dioxepan-2-one; U.S. Pat.No. 3,839,297 which discloses compositions comprisingpoly[L(−)lactide-co-glycolide] suitable for use as absorbable sutures;U.S. Pat. No. 3,297,033 which discloses the use of compositionscomprising polyglycolide homopolymers as absorbable sutures; U.S. Pat.No. 2,668,162 which discloses compositions comprising high molecularweight polymers of glycolide with lactide; U.S. Pat. No. 2,703,316 whichdiscloses compositions comprising polymers of lactide and copolymers oflactide with glydolide; U.S. Pat. No. 2,758,987 which disclosescompositions comprising optically active homopolymers of L(−) lactidei.e. poly L-Lactide; U.S. Pat. No. 3,636,956 which disclosescompositions of copolymers of L(−) lactide and glycolide having utilityas absorbable sutures; U.S. Pat. No. 4,141,087 which discloses syntheticabsorbable crystalline isomorphic copolyoxylate polymers derived frommixtures of cyclic and linear diols; U.S. Pat. No. 4,441,496 whichdiscloses copolymers of p-dioxanone and 2,5-morpholinediones; U.S. Pat.No. 4,452,973 which discloses poly(glycolic acid)/poly(oxyalkylene) ABAtriblock copolymers; U.S. Pat. No. 4,510,295 which discloses polyestersof substituted benzoic acid, dihydric alcohols, and glycolide and/orlactide; U.S. Pat. No. 4,612,923 which discloses surgical devicesfabricated from synthetic absorbable polymer containing absorbable glassfiller; U.S. Pat. No. 4,646,741 which discloses a surgical fastenercomprising a blend of copolymers of lactide, glycolide, andpoly(p-dioxanone); U.S. Pat. No. 4,741,337 which discloses a surgicalfastener made from a glycolide-rich blend of polymers; U.S. Pat. No.4,916,209 which discloses bioabsorbable semi-crystalline depsipeptidepolymers; U.S. Pat. No. 5,264,540 which discloses bioabsorbable aromaticpolyanhydride polymers; and U.S. Pat. No. 4,689,424 which disclosesradiation sterilizable absorbable polymers of dihydric alcohols.

[0051] Bioabsorbable polymers and polymer compositions are especiallyuseful when they comprise bioabsorbable fillers such as those describedin U.S. Pat. No. 4,473,670 (which is incorporated by reference) whichdiscloses a composition of a bioabsorbable polymer and a fillercomprising a poly(succinimide); and U.S. Pat. No. 5,521,280 (which isincorporated by reference) which discloses bioabsorbable polymers and afiller of finely divided sodium chloride or potassium chloride. Suchfillers can provide increased stiffness to bioabsorbable polymers andpolymer compositions.

[0052] Poly(glycolic acid) has a melting point of either 230° C. to 260°C. and a glass transition point of 45° C. to 50° C. (Materials SafetyData Sheet, Medisorb Lactide/Glycolide Polymers). If this is used as thesuture material, then in steps d) and e) of the methods of the inventionthe sources, the spacer member and/or the suture member should be heatedto at least this glass transition point temperature.

[0053] The bioabsorbable material should preferably maintain itsintegrity once implanted for from about 1 to 14 days. This helps toensure that the spacing of the sources is maintained for at least ashort period post-implantation. Use of the radioactive members of theinvention also helps ensure proper dosimetry and minimizes sourcemovement or shedding. Preferably the suture member should be fullyabsorbed by living tissue over a total of about 70 to 120 days.

[0054] By “essentially stiff” is meant that the suture member and thespacer member should have some structural integrity and be stiff enoughfor its proposed uses. The suture member and spacer member should bestiff enough to maintain the spacing between the radioactive seedsduring storage, shipment and implantation of the radioactive member. Ifthe suture member and spacer member have melted and deformed when heatedby the seeds so as to trap the radioactive seeds in place, it shouldthen re-stiffen when cooled.

[0055] In addition, the suture member should be formable into anelongate shape. Preferably, once in an elongate shape, the suture memberand the spacer member should be easy to cut using for example a scalpelor the like. Preferably, diameter of the spacer members is differentfrom that of the radioactive seeds, so that the spacer member can beeasily identified inside the suture material. For example, diameter ofthe spacer members can be 0.1 mm to 0.5 mm smaller than that of theradioactive seeds. Coloration in spacer members, such as violet, may beused to create a color scheme to easily identify components inside thesuture member. Dyed spacer members can be easily distinguished fromundyed suture member. The suture member should also preferably have anappreciable shelf life without the need for any special storage orhandling conditions. The suture member should also be sterilizable byany conventional sterilisation method, such as for example using steam,dry heat, ethylene oxide, electron-beam or gamma-radiation, as well aspulselight sterilization method. Preferred sterilization method isethylene oxide.

[0056] The suture member should have an internal diameter sufficient toaccommodate the radioactive seeds and spacer members. It may be of anysuitable cross-section, for example substantially circular,substantially circular with at least one flattened surface, orsubstantially polygonal, for example, square or triangular. A preferredsuture according to the invention has a substantially squarecross-section, both for ease of manufacture and to limit the surfacearea of the suture which will be in contact with the inside of thedispensing needle, so making jamming of the suture within the needle dueto friction between the needle and the surface of the suture lesslikely. Reduced friction could also be achieved with any cross-sectionhaving at least one flat surface e.g. a substantially circularcross-section flattened at a region on the circumference to give a flatsurface. Suitable sutures are substantially polygonal in shape, forexample, hexagonal, octagonal, or 12 or 16-sided etc. Thus, anotherpreferred suture in accordance with the invention is substantiallyoctagonal. A substantially triangular cross-section is also preferred,as it offers one less edge than a substantially square cross-section tocontact the inner walls of a delivery needle device.

[0057] The length of the suture member can vary. Preferably, aradioactive member contains 2 to 15 radioactive seeds.

[0058] The surface contact between the inner surface of a needle orother delivery device and a suture of any cross sectional shape can befurther minimized by the provision of suitable surface structures on thesuture surface which contacts the delivery device. For example, in thecase of a curved suture surface, surface contact can be reduced byincorporating ridges, spheres or other protrusions in the area of thesuture surface that contacts the needle or delivery device surface.Preferably, these surface structures comprise biocompatible orbiodegradable suture material. A suitable method for forming suchsurface structures comprises application of a heated mould or pressplate, the surface of which is configured as a negative of thestructures being applied to the suture. Upon application of the heatedmould to the surface of the suture, the suture will flow into thecavities in the negative mould. Release of the suture from the mould andcooling of the suture will impart to the suture surface a positiveimage, reciprocal to the negative image of the mould. Beads or bumpsproduced on the surface of the suture provide reduced contact area andless friction between the suture and a needle used as a delivery device.

[0059] Preferably, the suture will be visible using ultrasound imagingtechniques. For example, it may comprise sound reflecting particles orbubbles of gas which serve to enhance its ultrasound visibility. If thesuture is a polymer, bubbles of gas may be trapped in the polymer duringthe extrusion process to form a suture, for example by blowing bubblesinto the polymer as it is extruded. Alternatively, the polymer may beagitated (e.g. by sonication) prior to extrusion under a suitable gasatmosphere such that bubbles of gas are incorporated therein. Suitablegases include air, nitrogen, carbon dioxide, Freons™ and fluorocarbonssuch as perfluorobutane.

[0060] Alternatively, the suture member may be subjected to a gas underpressure, for example greater than atmospheric pressure, immediatelyprior to extrusion such that the gas becomes dissolved into thematerial. Upon extrusion combined with a reduction in the pressure ofgas due to warming (such as on extrusion into an ambient pressure andtemperature environment), the gas will expand to form bubbles in thesuture member. Preferably, the bubbles are at or near the surface of thesuture member.

[0061] The suture can be uniformly visible or non-uniformly visible byultrasound. For example, some regions of the suture may be more visibleby ultrasound than other regions. This can arise due to the presence ofregions where clusters of sound reflecting gas bubbles or particlesreside in a suture.

[0062] The suture may additionally or alternatively comprise particleswhich serve to enhance its visibility to ultrasound. Suitable particlesinclude particles of metal (for example titanium or aluminium), glass,silica, iron oxide, sand, clay, plastics such as TEFLON™, porousuniformly-sized non-aggregated particles as described in U.S. Pat. No.5,741,522 and U.S. Pat. No. 5,776,496 which are hereby incorporated byreference, hollow microcapsules or solid microspheres such as thosedisclosed in U.S. Pat. No. 5,648,095 which is hereby incorporated byreference, and microspheres of a fused sugar, a fused amino acid or ofPEG (polyethylene glycol).

[0063] One advantage of using imaging-visible, for exampleultrasound-visible, radioactive members of the invention inbrachytherapy is that the signal and image may be read, measured andanalysed by suitable computer software sufficiently quickly to allow aphysician to plan real-time dosimetry. This is advantageous from aclinical view point for both patient and medical personnel. However, themembers of the invention may be used in processes involving any type ofdosimetry mapping that uses information obtained due to the imagingvisibility of the radioactive seeds.

[0064] In addition, a physician may use the same imaging technique, forexample ultrasound, already in place during surgery to confirm bothorgan (e.g. prostate) position and size, and radioactive seedsplacement. This could enable a physician to calculate if additionalradioactive seeds need to be inserted, for example in situations wherethe dose pattern needs to be recalculated based on the actual, implantedposition of the sources.

[0065] The overall dimensions of the suture member should be such thatit will fit inside a dispensing needle or applicator cartridge. Forexample, if the internal diameter of a thin walled 18 gauge needle is0.102 cm (0.040 inches), then the effective maximum diameter of thesuture is preferably less than 0.102 cm (0.040 inches), so that it canbe dispensed from such needles.

[0066] The suture can be uniformly or non-uniformly distributedcross-sectionally around the sources. For example where the sources aresubstantially cylindical radioactive seeds, the shape of thecross-section of the internal surface of the suture could, preferably besubstantially round. In an alternative embodiment, the surface could besubstantially square.

[0067] Any conventional radioactive seed may be used as the radioactivesource. These include for example the radioactive seeds disclosed inU.S. Pat. No. 5,404,309, U.S. Pat. No. 4,784,116, U.S. Pat. No.4,702,228, U.S. Pat. No. 4,323,055 and U.S. Pat. No. 3,351,049 which arehereby incorporated by reference. By “seed” is meant any sealedcontainer, for example a metal container, containing or encapsulating aradioisotope. Suitable biocompatible container materials include metalsor metal alloys such as titanium, gold, platinum and stainless steel;plastics such as polyesters and vinyl polymers, and polymers ofpolyurethane, polyethylene and poly(vinyl acetate); composites such asgraphite; glass such as matrices comprising silicon oxide, and any otherbiocompatible material. Titanium and stainless steel are preferredmaterials for the containers.

[0068] The radioactive seeds may also comprise a suitable radioisotopeencapsulated within a polymer or ceramic matrix.

[0069] Typical radioactive seeds are substantially cylindrical in shape.Dimensions of a typical seed can be approximately 4.5 mm long with adiameter of approximately 0.8 mm.

[0070] Any radioisotope suitable for use in brachytherapy may be used inthe radioactive seeds. Non-limiting examples include palladium-103,iodine-125, strontium-89, sulphur-35, cesium-131, gold-198, thulium-170,chromium-56, arsenic-73, yttrium-90, phosphorus-32 and mixtures thereof.Especially preferred are palladium-103 and iodine-125. More than onetype of radioisotope may be present in the radioactive seeds for use inthe invention.

[0071] The radioactive seeds and spacer members are preferably loadedlinearly along the longest axis of the elongate suture member. Theorientation of the radioactive seeds relative to the suture will dependon the overall size and shape of the suture and the radioactive seeds.If the radioactive seeds are substantially cylindrical in shape, forexample if they are conventional seeds, then they are preferablyorientated with their longitudinal axes parallel to the longitudinalaxis of the elongate suture itself. Preferably, the radioactive seedsare regularly spaced, for example at intervals of between 0.6 and 1.2cm, preferably at about 1 cm intervals. A spacing of about 1 cm ispreferred if the sources are to be implanted for treatment of prostatecancer. Spacer members of suitable lengths are placed between seeds. Thenumber of radioactive seeds used for any particular application willdepend on the length of suture member used. Preferably, the radioactivemember is provided as a long strip which can then be cut or snapped tothe desired length for a particular application by the medical staff.

[0072] Preferably, all the radioactive seeds in one suture will containthe same radioisotope and/or be of the same radioactive strength. Ifmore than one type or strength of source is included in one suture, thenthe different radioactive seeds should be arranged in a regular patternto allow predictable dosing.

[0073] Preferably, the radioactive member may then be inserted into ajig to form a jig assembly. Such jigs disclosed in U.S. Pat. No.5,460,592 hereby incorporated by reference. FIG. 2 shows the radioactiveseed 2 of the radioactive member and its placement inside a jig 4. Thejig 4 allows for a fixed position of the radioactive seeds 2 and spacermembers 1, for subsequent manufacturing steps (stiffening),transportation and also for preparation of segments for implant(cutting).

[0074] The jig assembly is then dry heated. The dry heat causes thesuture member to become rigid. This stiffening process can take place ina process at 160° C. to 190° C. for 60 to 90 minutes.

[0075] As a still further feature of the invention there is provided afurther method for the production of a radioactive member for use inbrachytherapy comprising a hollow elongate bioabsorbable suture memberwith radioactive seeds and spacer members disposed alternately therein,said method comprising the steps of:

[0076] a) providing an elongate preferably single stranded bioabsorbablesuture member having a longitudinal groove or slot therein,

[0077] b) providing a plurality of radioactive seeds,

[0078] c) providing a plurality of bioabsorbable spacer members, whereinthe spacer members are of a different color from that of the radioactiveseeds and of different diameter from that of the radioactive seeds;

[0079] d) placing the radioactive seeds and the spacer memberssequentially or concurrently into the groove in the suture member suchthat the radioactive seeds and the spacer members are securely retainedwithin the groove.

[0080] Preferably, the groove or slot will be diametrically opposed to aflat surface of the cross section of the suture. For example, where thesuture is substantially round with one flattened surface, the groove orslot will be positioned opposite to this flat surface. This would allowfor ease of orientation during manufacture for example, the suturemember could be orientated with the slit uppermost using the flatsurface for reference so that the sources could be readily pushed intothe groove.

[0081] Preferably, the groove or slot will be shaped such that once asource is placed therein it is securely retained. For example, theopening to the groove may be slightly narrower than the groove itselfand the width of the source such that the source must be “clipped” intoplace by pushing it through the opening, and is then retained within thegroove. For example, a rail or elongate lip may be formed along the longaxis of the suture inside the groove and adjacent to the opening of thegroove, such that the radioactive seeds and the spacer members, oncepushed past the rail or lip, are held in place inside the groove by therail or lip. Alternatively, a series of suitably spaced protrusions, forexample knobs or tabs, may be provided just inside the opening of thegroove to hold the sources in place within the groove. Preferably, therails, lips or protrusions will be formed on both sides of the openingto the groove.

[0082] Alternatively or additionally, the radioactive seeds and spacermembers may be held in place by a suitable biocompatible adhesive. Forexample, a bead of a suitable adhesive or resin could be placed in thegroove with a source and then the adhesive or resin allowed to dry or acuring method used to dry it. Examples of suitable biocompatibleadhesives are known in the art and include epoxy adhesives such asTra-Bond 2105, a two part epoxy adhesive from Tra-Bond US (see Chem.Eng. News, 8 Dec. 1997, 75 (49) p 40, hereby incorporated by reference);certain tyrosine- and lysine-containing heptapeptides and polypeptidesas disclosed in Japanese Patent 05017499, hereby incorporated byreference; certain adhesives derived from polyphenolic proteins asdisclosed in U.S. Pat. No. 5,015,677, hereby incorporated by reference;certain dental cement adhesives such as an adhesive compositioncomprising poly(methyl methacrylate) (PMMA) and 5% of5-methacryloxyethyl trimellitic anhydride with partially oxidizedtibutylborane as disclosed in Proc. IUPAC, I.U.P.A.C., Macromol. Symp.,28^(th) (1982), 395, hereby incorporated by reference; and poly(propylmethacrylate), poly(methyl methacrylate), poly(butylmethacrylate-co-ethyl methacrylate), and silicone gels (see Proc.SPIE-Int. Soc. Opt. Eng, (1998), 3258, 164-168, hereby incorporated byreference).

[0083] Alternatively or additionally, the edges of the groove can bedeformed or pinched together by application of an external force, forexample by applying a compression step in which the upper portion of thegroove edges above the widest part of the source are contacted with oneor more warmed or heated plates, baffles, flanges or diverting memberswhich may, for example, comprise two plates oriented parallel to theaxis of the suture and substantially perpendicular to a projected radiusof the radioactive seeds and to each other such that interaction withthe groove edges produces a narrowing of the opening in the groove. Thiscan be done after the source is placed in the groove. Alternatively, arotating heated roller or wheel, configured to apply compression to thegrooves in the above manner may be used. The edge of the roller or wheelmay be concave to achieve this compression. The compression may becontinuous.

[0084] Alternatively, heated plates can be used to bend the edges of thegroove after a source is placed into the groove. In a grooved opening ofa suture material, the edges of the groove can be substantiallyperpendicular to the base of the groove. The edges of the groove canextend beyond the midpoint of the source, for example beyond the widestpart of the source (such as the diameter of a substantially circularsource) when viewed from the end of the source when the source is placedinto the groove. With the source in the groove, heated plates, baffles,flanges or diverting members can be applied from above or beside thevertical groove edges to contact the vertical edges above the widestpart of the source. The heated plates then soften the vertical grooveedges and the mechanical force causes the edges to bend over the source,thereby pinching the source in place. Removal of the heated platesallows the bent edges to cool and thenceforth hold the source tightly inplace in the grooved suture.

[0085] In another embodiment, a heated rotating wheel or rollerconfigured to apply compression to the upper edges of the groove may beused to narrow the opening of a groove after a radioactive seed has beenplaced therein. A suture with one or more radioactive seeds and spacermembers in place within the groove may be fed under a heated rotatingwheel or roller, such that part of the wheel or roller contacts the areaof the suture adjacent to the opening of the groove, causing it tosoften or melt and so deform around the source to hold it in place.Preferably, the part of the roller or wheel contacting the suture willhave a concave surface such that the edges of the groove may be deformedor pinched together to form a completely or partially closed tubecontaining the sources. Contact between a given portion of the sutureand the wheel or roller can be temporary as the wheel or roller rotates.Optionally, the suture may be constrained to bend and follow thecircumference of the wheel or roller and be held under tension tostretch, compress or further form it.

[0086] The suture may be fed under the wheel or roller in a continuousprocess. Optionally, the part of the wheel or roller contacting thesuture may comprise a positive or negative mould such the contact withthe suture transfers a reciprocal pattern, for example comprising ridgesor bumps, to the suture.

[0087] Alternatively or additionally, after loading with radioactiveseeds and spacer members, the suture can be encased within a suitablecoating, for example of Vicryl™ braid, to hold the radioactive seeds andspacer members in place inside the groove or the discrete openings.

[0088] At the end of the manufacturing process, the radioactive membermay be cut to suitable lengths and each length loaded separately into ajig, such as the jig disclosed in U.S. Pat. No. 5,460,592. The jigassembly can then be stiffened by a dry heat process as described in aprevious embodiment.

[0089] Optionally, the radioactive member of the invention will beshielded for shipping from the manufacturing site to the site of use.Preferably, after packaging, the product will be sterilized, for exampleby any conventional sterilisation procedure such as autoclave, gammairradiation, ethylene oxide sterilisation or pulse light sterilization.The product can then be shipped from the manufacturer to the site of useas a sterile unit which, once removed from the packaging and shielding,is ready for the member to be used.

[0090] The radioactive members of the invention may be used in thetreatment of a range of conditions including head and neck cancers(including those of the mouth, lips and tongue) brain tumours, lungtumours, cervical tumours, vaginal tumours and prostate cancer. They maybe used as a primary treatment (for example in the treatment of prostatecancer or unresectable tumours) or for treatment of residual diseaseafter excision of the primary tumour. They may be used concurrentlywith, or at the completion of, other treatment modalities, for exampleexternal beam radiation therapy, chemotherapy or hormonal therapy.

[0091] The radioactive members of the invention may be used alone or incombination with individual radioactive sources, for example seeds.

[0092] As a further aspect of the invention, there is also provided amethod of treatment of a condition which is responsive to radiationtherapy, for example cancer or arthritis, especially prostate cancer,which comprises the placement of a radioactive member comprising anessentially stiff elongate, single stranded bioabsorbable suture memberwith spaced radioactive sources disposed therein at or adjacent the siteto be treated within a patient for a sufficient period of time todeliver a therapeutically effective dose.

[0093] In a preferred embodiment, the radioactive member may bevisualised using a suitable imaging technique, preferably ultrasoundimaging, in connection with real-time dosimetry equipment.

[0094] The radioactive members of the invention may be administered to apatient by placing a suitable length of suture into the tip of a hollowneedle and then placing a stylet into the needle, as shown in FIG. 3.The needle 5 may be inserted into a patient and then pulled back overthe stylet leaving the suture in place. For methods of administrationsee, for example, A. van't Riet et al., Int. J. Radiation Oncology Biol.Phys., Vol. 24, pages 555-558, 1992, hereby incorporated by reference.

[0095] For example, radioactive member 7 can be prepared to the requiredlength according to the prescribed implant plan. This preparationincludes removing the radioactive member from the packaging andsterility barrier and cutting through a spacer member to the prescribedlength. The radioactive member, cut to the prescribed length, is theninserted into an insertion needle, through a hub end 6 thereof, to thepoint where the entire assembly is completely inside the needle 5. Theradioactive member is then pushed through the hollow insertion needle,with a needle stylet, until the leading tip of the radioactive memberreaches a needle plugging media, such as bone wax. The loaded insertionneedle is then inserted into a prescribed treatment area of a patient,for example, prostate. The insertion needle is subsequently removed,leaving the radioactive member in the prescribe treatment area. Theradioactive member is provided sterile for immediate preparation anduse.

[0096] An alternate method of insertion needle loading would include theuse of an after-loading device, as shown in FIG. 4. In this embodiment,the insertion needle 5 can be inserted into the prescribed treatmentarea of a patient, for example, prostate, in advance of loading theradioactive member, following the pre-operative implant plan. Theradioactive member 7, prepared to the prescribed length, is then loadedinto an after-loading device 8, which temporarily houses the radioactivemember. When required, the radioactive member is then transferred to theinsertion needle where it mates into the insertion needle hub. A styletis then used to advance the radioactive member through the after-loadingdevice, into the needle, and finally into the patient.

[0097] The invention described and claimed herein is not to be limitedin scope by the specific embodiments herein disclosed, since theseembodiments are intended as illustration of several aspects of theinvention. Any equivalent embodiments are intended to be within thescope of this invention. Indeed, various modifications of the inventionin addition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are also intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A radioactive member for use in brachytherapycomprising a hollow elongate bioabsorbable suture member with aplurality of radioactive seeds and spacer members disposed alternatelytherein, wherein the spacer members are dyed with a different color fromthat of the undyed radioactive seeds and of different diameter from thatof the radioactive seeds.
 2. A radioactive member of claim 1, whereinthe diameter of the spacer member is 0.1 mm to 0.5 mm smaller than thatof the radioactive seeds.
 3. A radioactive member of claim 1, whereinthe spacer member is dyed with violet.
 4. A radioactive member asclaimed in claim 1 wherein the suture member comprises poly(glycolicacid), poly(lactic acid), a polyester amide of glycolic or lactic acid,or a polydioxanone.
 5. A radioactive member as claimed in claim 1wherein the carrier material has a substantially circular cross section.6. A radioactive member as claimed in claim 1 characterised in that thecross section of the carrier has at least one flat surface.
 7. Aradioactive member as claimed in claim 1 wherein the carrier has asubstantially polygonal cross-section and is, preferably, substantiallyoctagonal, square or triangular.
 8. A radioactive member as claimed inclaim 1 wherein the carrier comprises ultrasound reflecting particles orbubbles of gas.
 9. A radioactive member for use in brachytherapycomprising a hollow elongate bioabsorbable suture member with one ormore slots therein in which one or more radioactive seeds and spacermembers are disposed alternately in a spaced relationship, wherein thespacer members are dyed with a different color from that of the undyedradioactive seeds and of different diameter from that of the radioactiveseeds.
 10. A method for the production of a radioactive member for usein brachytherapy comprising an elongate, bioabsorbable suture memberwith radioactive seeds and spacer members disposed alternately therein,said method comprising the steps of: a) providing a hollow bioabsorbablesuture member, providing a plurality of radioactive seeds; c) providinga plurality of bioabsorbable spacer members, wherein the spacer membersare dyed with a different color from that of the undyed radioactiveseeds and of different diameter from that of radioactive seeds; d)heating the radioactive sources to a temperature above the melting orsoftening temperature of the suture material; e) placing the heatedsources and spacer members alternately onto the suture memberin apredetermined pattern whereby the suture membermelts or deforms aroundeach source and spacer member; and f) cooling the suture member suchthat it solidifies or hardens about each source and spacer member so asto securely retain each source in place.
 11. A method of claim 10,wherein the diameter of the spacer member is 0.1 mm to 0.5 mm smallerthan that of the radioactive seeds.
 12. A method of claim 10, whereinthe color of the spacer member is dyed with violet.
 13. A method ofclaim 10, further comprising a step of sterilizing the radioactivemember.
 14. A method for the production of a radioactive member for usein brachytherapy comprising a hollow elongate bioabsorbable suturemember with radioactive seeds and spacer members disposed alternatelytherein, said method comprising the steps of: a) providing an elongatepreferably single stranded bioabsorbable suture member which is at atemperature above its melting or softening temperature, b) providing aplurality of radioactive seeds, c) providing a plurality ofbioabsorbable spacer members, wherein the spacer members dyed with adifferent color from that of the undyed radioactive seeds and ofdifferent diameter from that of the radioactive seeds; d) optionallyheating the radioactive seeds and/or spacer members to a temperatureabove the melting or softening temperature of the suture member; e)alternately placing the (optionally heated) radioactive seeds and spacermembers onto the suture member whereby the suture member melts ordeforms around the radioactive seeds and spacer members; and f) coolingthe suture member such that it solidifies or hardens about each sourceand spacer member so as to securely retain each radioactive seeds andspacer member in place.
 15. A method for the production of a radioactivemember for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with radioactive seeds and spacer membersdisposed alternately therein, said method comprising the steps of: a)providing an elongate preferably single stranded bioabsorbable suturemember having a longitudinal groove or slot therein; b) providing aplurality of radioactive seeds, c) providing a plurality ofbioabsorbable spacer members, wherein the spacer members dyed with adifferent color from that of the undyed radioactive seeds and ofdifferent diameter from that of the radioactive seeds; d) placing theradioactive seeds and the spacer members sequentially or concurrentlyinto the groove in the suture member such that the radioactive seeds andthe spacer members are securely retained within the groove.
 16. A methodas claimed in claim 15 wherein the radioactive seeds and the spacermembers are retained in the groove using a biocompatible adhesive orresin.
 17. A method as claimed in claim 15 wherein the radioactive seedsand the spacer members are retained in the groove by means of one ormore rails, lips, tabs or knobs.
 18. A method of claim 15, wherein itfurther comprises a step of providing means to apply an external forceto deform the edges of the groove around the radioactive seeds and thespacer members such that each radioactive seed and spacer member aresecurely retained in the groove.
 19. A method of claim 18, wherein themeans comprises a heated plate, baffle, flange, wheel or roller.
 20. Amethod of claim 19 wherein the means comprises a concave surface.
 21. Amethod of treatment of a condition which is responsive to radiationtherapy which comprises the placement of a radioactive member of claim 1disposed therein at or adjacent the site to be treated within a patientfor a sufficient period of time to deliver a therapeutically effectivedose.
 22. A method of treatment of claim 21 wherein the condition totreated is prostate cancer.
 23. A method of claim 22 wherein theradioactive member is visualized using a suitable imaging technique inconnection with real-time dosimetry equipment.
 24. A method of claim 23wherein the imaging technique comprises ultrasound imaging.
 25. Aradioactive member of claim 1 loaded onto a wheel or a jig.
 26. Aradioactive member of claim 25 wherein the wheel or jig is shielded. 27.A method of using a radioactive member for brachytherapy, said methodcomprising: a) cutting the radioactive member at one of the spacermembers to a prescribed length according to the prescribed implant plan;b) inserting the cut radioactive member into a hub end of a hollowinsertion needle suitable for insertion into a prescribe treatment area,so that the entire radioactive member is inside the needle; c) pushingthe radioactive member through the hollow insertion needle with a needlestylet, until the leading tip of the radioactive member reaches a needleplugging media; d) inserting the loaded insertion needle into theprescribed treatment area of a patient; e) removing the insertion needlefrom around the radioactive member, leaving the radioactive member inthe prescribed treatment area of the patient.
 28. A method of using aradioactive member for brachytherapy, said method comprising: a)inserting an insertion needle into a prescribed treatment area of apatient; b) cutting the radioactive member at one of the spacer membersto a prescribed length according to the prescribed implant plan; c)loading the radioactive member into an after-loading device; d)transferring the radioactive member in the after-loading device to theinsertion needle where it mates into the insertion needle hub; e)applying a stylet to advance the radioactive member through theafter-loading device into the insertion needle, and finally into thepatient; f) removing the insertion needle and the after-loading device.